Stimulation of subcortical brain regions using transcranial rotating permanent magnetic stimulation (trpms)

ABSTRACT

A method of affecting a biological, cellular or biochemical function or structure in a targeted subcortical location in a brain of a patient using a TRPMS apparatus placed on a head of the patient includes positioning two or more of a plurality of magnetic assemblies on locations of the head mount selected to stimulate the targeted subcortical location in the brain of the patient, and activating the plurality of magnetic assemblies at the selected locations to generate magnetic fluxes of a selected strength, frequency and duration directed into the brain of the patient,/wherein the magnetic flux directed into the brain of the patient from each of the assemblies is operative to generate induced electric field in regions of the brain and the regions of induced electric fields generated by each of the plurality of magnetic assemblies converge in the targeted subcortical location and combine to a magnitude sufficient to affect the biological, cellular or biochemical function or structure in the targeted subcortical location.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/730,266, filed on Dec. 30, 2019, titled STIMULATION OF SUBCORTICALBRAIN REGIONS USING TRANSCRANIAL ROTATING PERMANENT MAGNETIC STIMULATION(TRPMS), which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to medical devices, and more particularly,relates to a system and method for neurostimulation of electrical orelectrochemical activity in cortical or subcortical brain regions byapplication of convergent magnetic fields generated by a plurality ofmagnetic assemblies in a Transcranial Rotating Permanent MagneticStimulation (TRPMS) apparatus.

BACKGROUND OF THE INVENTION

Commonly-owned U.S. Pat. No. 9,456,784, entitled “Method and Apparatusfor Providing Transcranial Magnetic Stimulation (TPMS) to a Patient”describes a transcranial rotating permanent magnetic stimulationapparatus (“TRPMS apparatus”) that includes replaceable magnetassemblies that can be used to generate various patterns of transcranialmagnetic stimulation. FIG. 1 is a side view of an example TRPMSapparatus 5. As shown, the TRPMS apparatus 5 includes a head mount orcap 10 for positioning on a subject's head and a plurality of magnetassemblies 15 that can be attached at specific attachment locations e.g.A, B, C, D, E, F to the surface of the head mount (in FIG. 1, magneticassemblies are shown attached at locations A, C and E, obscuring theattachment points). The magnet assemblies are connected by leads 25 to acomputer device (not shown in FIG. 1). The computer device can beprogrammed to activate any or all magnet assemblies to generatetranscranial magnetic stimulation suited for a specific treatment. Forexample, the computer device can control magnets at different locationsto deliver different magnitudes of stimulation, or to generateparticular waveforms of stimulation (e.g., in periodic bursts oroscillatory waves) suited for stimulating activity in specific brainregions.

These waveforms are applied to the magnetic assemblies to set them intomotion and to control rotation in order to deliver highly focal stimuli.The various parameters for controlling the magnetic assemblies, whichinclude the waveforms (which can be applied in packet bursts), dutycycles, magnitudes, and rate of rotation, are tailored to the particulartreatment or therapy contemplated. As such, the demands on the magneticassemblies can vary depending on the intended treatment. Commerciallyavailable magnetic assemblies preferably are labeled as being approvedfor particular uses and for a finite number of times before beingdiscarded.

Thus far, the magnetic assemblies using permanent magnets have been usedfor low-depth cortical stimulation. However, there are conditions forwhich shallow-depth stimulation does not produce therapeutic results.What is therefore needed is a system and method that providesstimulation of deeper areas of the brain for therapeutic, diagnostic andother purposes.

SUMMARY OF THE INVENTION

The present disclosure provides a method of stimulating or otherwisebioelectromagnetically affecting a biological, cellular or biochemicalfunction or structure in a targeted subcortical location in a brain of apatient using a TRPMS apparatus provided on a head mount having aplurality of releasable magnetic assemblies with rotating permanentmagnets operable to rotate for controlled durations and spin rates. Themethod comprises positioning two or more of the plurality of magneticassemblies on locations of the head mount selected to affect thebiological, cellular or biochemical function or structure at thetargeted subcortical location in the brain of the patient, andactivating the plurality of magnetic assemblies at the selectedlocations to generate magnetic fluxes of a selected strength, frequencyand duration directed into the brain of the patient, wherein themagnetic flux directed into the brain of the patient from each of theassemblies is operative to generate induced electric field in regions ofthe brain. The regions of induced electric fields generated by each ofthe plurality of magnetic assemblies converge and overlap in thetargeted subcortical location and combine to a magnitude sufficient(i.e., as strong as necessary) to stimulate neurons or to modulatebiological, cellular and/or biochemical processes within brainstructures in the targeted subcortical location. It is also noted thatthe strength of the induced electric fields in regions outside of theregion of overlap is minimized to avoid unwanted stimulation of brainstructures outside of the region in which the convergent filed overlap.

The present disclosure further provides an apparatus for stimulating orbiomagnetically affecting a biological, cellular or biochemical functionor structure in a targeted subcortical location in a brain of a patient.The apparatus comprises a head mount positioned on the patient, and aplurality of releasable magnetic assemblies coupled to the head mountincluding rotating permanent magnets operable to rotate for controlleddurations and spin rates, the plurality of magnetic assemblies beingselectively positioned at locations of the head mount to stimulate oraffect the targeted subcortical location in the brain of the patient.Activation of each of the plurality of magnetic assemblies at theselected locations causes magnetic fluxes of a selected strength,frequency and duration to be directed into the brain of the patient,wherein the magnetic flux directed into the brain of the patient fromeach of the assemblies is operative to generate induced electric fieldin regions of the brain. The regions of induced electric fieldsgenerated by each of the plurality of magnetic assemblies converge andoverlap in the targeted subcortical location and combine to a magnitudeas strong as necessary to stimulate neurons or to modulate biological,cellular and/or biochemical processes within brain structures in thetargeted subcortical location.

These and other aspects, features, and advantages can be appreciatedfrom the following description of certain embodiments of the inventionand the accompanying drawing figures and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an example transcranial rotating permanentmagnetic stimulation (TRPMS) apparatus that can be used in the contextof the present invention.

FIG. 2 is a schematic plan view of an example transcranial magneticsystem that can be used in the context of the present invention.

FIG. 3A presents a block diagram illustrating an exemplary magneticassembly device.

FIG. 3B is a schematic block diagram of an attachment point of a headmount according to an embodiment of the present invention.

FIG. 4 is a schematic illustration showing magnetic fields produced bythree magnets and the penetration of the fields in the brain of thepatient.

FIG. 5 is a graph showing an example of an oscillatory waveform ofvoltages induced by TRPMS magnets at a stimulation site.

FIGS. 6A and 6B are graphs of induced electric field versus distance inthe X plane (FIG. 6A) and Y plane (FIG. 6B).

FIG. 7 is graph of induced electric field verse depth at low scaling andhigh scaling.

FIG. 8A is a schematic cross-sectional view of magnetic assembliespositioned on the skull of patient delivering non-convergentneurostimulation.

FIG. 8B is a schematic cross-sectional view of magnetic assembliespositioned on the skull of patient delivering convergentneurostimulation by additive induction of electric fields at subcorticaldepth.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The following description discloses a TRPMS apparatus and method forstimulating or otherwise bioelectromagnetically affecting a biological,cellular or biochemical function or structure in a targeted cortical orsubcortical brain regions using a plurality of magnetic assembliesmounted on the skull of a patient. The term “bioelectromagnetically” asused herein means pertaining to the interaction between an externalmagnetic field and biological tissues, structures and functions. Themagnetic assemblies employ rotating permanent magnets to generatetime-varying magnetic fields that induce electric currents at a targetedlocation in the brain of the patient. TRPMS has the advantage that thespatial spread of the magnetic field and induced current is more limitedin comparison to related methods such as TMS, which employselectromagnetic coils. On the other hand, TRPMS suffers from thedisadvantage that magnetic field strength tends to be lower than TMS.This disadvantage is overcome by employing multiple magnetic assembliesto generate magnetic fields that, at least in part, converge at thetarget location. By such convergence, the magnetic fields produced bythe distinct assemblies combine according to the principle ofsuperposition to boost the magnetic field strength to levels sufficientto achieve changes in the frequency of fasciculation potentials orspontaneous motor unit potentials (sMUPs) in localized cortical orsubcortical regions. Additionally, in certain applications the magneticfield strength is applied at a level as strong as necessary to modulatebiological, cellular and/or biochemical processes within brainstructures.

The following sections discuss an exemplary embodiment of a TRPMSapparatus that can be used in the context of the methods disclosedherein. FIG. 2 is a schematic plan view of an example transcranialmagnetic system 200. A harness, head mount or cap 205 (“head mount”) isconfigured with a plurality of attachment points e.g., 211, 213, 215,217 where one or more respective magnetic assembly devices 212, 214,216, 218 can be detachably connected. In certain implementations, themagnetic assembly devices are connected to the head mount using hook orloop type fasters such as Velcro. The attachment points representspecific locations on the head mount and both the number of magneticassembly devices used, and the positions at which they are deployed atthe attachment point on the head mount, depend on the medical conditions(treatment) for which the TRPMS is applied. In some embodiments, theattachment points can be at predetermined positions on the head mountsurface. The head mount can also be equipped with rails, channels orsimilar structures containing conductive elements that enable a givenmagnetic assembly device to be secured at variable points along thechannel or rail, depending on the desired treatment location or thecranial structure of a given subject. In such an embodiment, a rheostator equivalent circuit can be employed to electronically identify thevariable location of a given magnetic assembly on the head mount 205.The attachment points can all be of like design to permit a standardmagnetic assembly device to be attached anywhere along the head mount205, or the attachment points can provide more than one fitting to onlymate with corresponding magnetic assembly devices.

The attachment points, 211, 213, 215, 217 which correspond to regions onthe cranium where magnetic fields are applied, are optimized fordelivery of magnetic energy for a given diagnosis, therapy, mapping, orother application. The arrangement shown in FIG. 2 is exemplary and itwill be appreciated that numerous other configurations can be employeddepending on the intended application. The magnetic assembly devices arecontrolled (i.e., activated, driven and deactivated) by a control device230 that includes a controller interface 232 (“controller”) that iselectrically coupled to each of the magnetic assembly devices 212, 214,216, 218.

FIG. 3A provides a more detailed illustration of an exemplary magneticassembly device e.g., 212. The magnetic assembly device includes anactuator device 302 which can be implemented as a motor, such as astepper or bushed motor that can run at variable speeds, for example, upto 24,000 revolutions per minute (RPM). Other actuator device typesknown to those of skill in the art can be utilized in certainembodiments. The actuator device 302 is electrically coupled to thecontroller 232 from which it receives electrical signals that drive theactuator device. The actuator device 302 is mechanically and rigidlycoupled to a magnet 304, such as via a rotor shaft, and is arranged tocause the magnet 304 to rotate when driven by control signals from thecontroller 232.

In accordance with various embodiments, the magnet 304 can beimplemented as a permanent magnet of a variety of different sizes andstrengths. The permanent magnet 304 can be composed of a rare earthmaterial such as neodymium. In an alternative arrangement, the magnet304 can be implemented as a soft magnetic composite (“SMC”) magnet. Incertain implementations, the magnets can be cylindrical (¼ in. by ⅜ in.)axially magnetized neodymium magnets (N52 grade) manufactured by K&JMagnetics of Jamison, Pa.

Rotation of the magnet 304 creates a rapidly changing magnetic field. Insome embodiments, each of the magnet assembly devices provide a rapidlychanging magnetic field of at least 500-600 Tesla/second and a magnetmovement speed of no less than 400 Hertz. As will be appreciated bythose knowledgeable in the field of TRPMS, the changing magnetic fieldgenerated by the rotating permanent magnets induces electric fieldswithin the brain of the patient. More specifically, the changingmagnetic fields can induce changes in fasciculation potentials orspontaneous motor unit potentials (sMUPs) in focused cortical orsubcortical locations in the brain. Such changes can, in certaininstances, provide therapeutic or other beneficial effects.

The apparatus can be used for targeted therapies, assisting indiagnosis, mapping out brain function for use in neuroscience research;non-medical applications of the apparatus can include stimulating areasof the brain to improve learning, concentration and education. Asdefined herein, medical applications can be considered treatments for asubject with a known or possible disease, condition, handicap, or other“sub-normal” attribute, while non-medical applications can include thosein which the subject may or may not have or be diagnosed with any suchconditions or attributes, but wishes to test or improve mentalfunctioning in some manner. Non-medical applications can improvephysical function as well, including such characteristics ascoordination, speed, and stamina. It should be understood that for somesubjects and in some instances, for example, with respect to subjectshaving very slight or imagined conditions or handicaps, this distinctioncan be blurred.

Medical applications include, but are not limited to, Tic Disorders andTourette Syndrome, Parkinson's disease and other movement disorders suchas Dystonia, Tremor and Ataxia, motor neurone diseases such asamyotrophic lateral sclerosis and multiple sclerosis, epilepsy, migraineand other headaches, complex regional pain syndrome (CRPS), neuropathyand fibromyalgia, tinnitus, stroke, psychological disorders includingmajor depressive disorder and treatment resistant depression, anxietydisorders, obsessive compulsive disorder, eating disorders such asanorexia and bulimia, post-traumatic stress disorder (PTSD), psychiatricdisorders including schizophrenia and bipolar disorder; visual, auditoryand other hallucinations secondary to psychiatric disorders, attentiondisorders such as ADHD, substance abuse and addictions, learningdisorders such as dyslexia and dysgraphia; speech disorders such asstuttering, memory disorders, dementia including Alzheimer's disease,traumatic brain injury, autism spectrum disorder, disorders ofconsciousness, and urinary incontinence. Recent studies have shown thatTRPMS can be used for oncological therapy due to the effect that therapidly changing magnetic fields have upon mitochondrial oxidation. Inaddition, magnetic fields are known to affect the position and alignmentof polar molecules. Since cellular processes such as cell divisionutilize the properties of polar molecules, application of magneticfields can disrupt or otherwise affect these processes. For example,cell division relies upon a particular positioning and alignment ofpolar septin and tubulin molecules. Use of convergent magnetic fieldscan thereby be used to affect cell division in target regions. Inoncological treatments, the disrupting of cell division can possiblyslow down tumor growth.

Non-medical applications include, but are not limited to, improvement orother modulation of: mood; attention and focus; motor and cognitivefunctions; anxiety such as social shyness; depression; memory andlearning; smoking cessation, alcoholism and other addiction; and PTSD.Further non-medical applications include training and improvement ofphysical abilities and skills such as coordination and speed. This ismade possible by the close connection between biological motor activityand electrical stimulation.

While the apparatus above is configured to conform to a patient'scranium and to apply magnetic fields into the patient's brain, similarconfigurations of magnetic assemblies and mounts can be placed on otherportions of the anatomy to induce electric fields in tissues therein.For example, the magnetic assemblies and mounts can be fitted securelyon straps, or other features that can cover appendages, gastrointestinalareas, the thorax (lungs, heart) and spinal areas. These areas can alsobe treated for medical or non-medical purposes using the magneticassemblies.

In one exemplary configuration of the magnetic assembly device, theactuator device 302 may comprise both a motor for rotating the magnetand a lateral movement device (not shown) for changing the position ofthe magnet relative to the subject, such as solenoid. In this exemplaryconfiguration, the lateral movement device in the magnetic assemblydevice can position the magnet closer or further away from brain of thesubject. Whether and when there is lateral movement can be dependentupon particular treatment parameters that a user is applying to thesubject. The lateral movement device optionally enables azimuthadjustment in addition to or as the lateral movement itself.

The magnetic assembly device 212 also includes one or more sensors 306that can be used to monitor the magnetic field, the temperature of theassembly device, the current induced in the brain, or other data pointsregarding the assembly or the subject. Such data can comprisebiophysical data as is known to those of skill in the art. In onearrangement, the sensors 306 comprise an array of one or more electrodesthat are configured to measure electrical activity of the brain and tosend the measured data as electrical signals back to the controller 232.The data gathered can be packaged, if desired, and uploaded to apersistent data store, which may be local or remote to the controldevice, e.g., to serve as supporting data with regard to the safety orefficacy of a particular treatment protocol unit or treatment protocol.Additionally, magnetic assembly device 212 includes an identificationelement, such as an RFID or QR tag and/or a memory unit (chip or card)that uniquely identifies each device. The memory unit is coupled to astandard port to allow the memory unit to be read externally. In someembodiments, the tag can be placed on the outer housing of the device orother accessible location. In other embodiments, the memory unit can beread by the controller 232 in order to determine the identifier of themagnetic assembly device.

Returning to FIG. 2, the controller 232 communicates with one or more ofthe magnetic assembly devices 212, 214, 216, 218 through a wired orwireless link or combinations thereof. The controller 232 communicateswith the magnetic assembly devices using separately controllablecommunication links, one for each magnetic assembly device e.g., 212,214. In addition, in some embodiments, the controller 232 can receiveelectrical signals from the attachment points e.g., 211, 213, 215, 217whenever the magnetic assembly devices are being deployed. In certainconfigurations, however, the controller 232 can communicate with themagnetic assembly devices through the use of various combinations of oneor more conduits, USB, serial, or wired or wireless communication linksthat are known to those of ordinary skill in the art.

FIG. 3B illustrates an exemplary embodiment of an attachment point 211that can be used in the context of the present invention. Attachmentpoint 211 includes an opening 332 in which a mounting element of amagnetic assembly device can be received (an example mounting element isshown in outline). Electrical contacts 335, 337 can be disposed atopposite edges of opening 332, as shown. A first electrical lead 341 iscoupled to electrical contact 335, and a second electrical lead 343 iscoupled to electrical contact 337. The controller 232 is coupled to theelectrical leads 341, 343. A circuit component 350, which can be aresistor, capacitor, or inductive element, is coupled to electrical lead341 and has a second coupling to cause the component to either be inparallel or in series with any particular mounted magnitude assemblydevice. When the mounting element of a magnetic assembly device ismounted into the opening, the mounting element, which is conductive,effectively closes the circuit by allowing current to flow in thechannel between the contacts 335, 337 and the electrical leads 341, 343.In addition, when the magnetic assembly device is mounted, and thecircuit is closed, a current or voltage signal flowing is modified bythe circuit component 350 which is arranged either in parallel with thechannel through the attachment point or in series, depending on theparticular implementation. The properties of the circuit (e.g.,resistance, impedance, capacitance, reactance) component 350 are chosento be unique to the attachment point. Accordingly, the magnitude, phase,or both magnitude and phase of the modification of the current/voltagesignal by the component of attachment point 211 is different from themagnitude or phase of the modification of all the other attachment pointin the apparatus, which include circuit components with differentcharacteristics. In this manner, each attachment point provides a uniquecurrent/voltage signature allowing the controller 232 to monitor eachattachment point, and to determine when a magnetic assembly device hasbeen mounted into any of the attachment points.

Returning again to FIG. 2, the controller 232 may comprise ports,drivers, gate arrays, logic switches or other devices configurable toselectively energize one or more magnet assembly devices 212, 214, 216,218 in response to an instruction set or command signal from a processor234 of the control device 230 and to receive electrical signalstherefrom and from attachment points 211, 213, 215, 217. In oneimplementation, the controller 232 and processor 234 are part of asingle computing device. In other implementations, the controller 232and processor 234 can be housed in separate devices that areelectrically connected.

The control device 230 can be a desktop or workstation class computerthat executes a commercially available operating system, e.g., MICROSOFTWINDOWS, APPLE OSX, UNIX or Linux based operating systemimplementations. In accordance with further embodiments, the controldevice 230 can be a portable computing device such as a smartphone,wearable or tablet class device. For example, the control device 230 canbe an APPLE IPAD/IPHONE mobile device, ANDROID mobile device or othercommercially available mobile electronic device configured to carry outthe processes described herein. In other embodiments, the control device230 comprises custom or non-standard hardware configurations. Forinstance, the control device 230 can comprise one or moremicro-computer(s) operating alone or in concert within a collection ofsuch devices, network adaptors and interfaces(s) operating in adistributed, but cooperative, manner, or array of other micro-computingelements, computer-on-chip(s), prototyping devices, “hobby” computingelements, home entertainment consoles and/or other hardware.

The control device 230 can be equipped with a persistent memory device236 that is operative to store the operating system in addition to oneor more of software modules, such as those described herein to implementtranscranial magnetic stimulation in accordance with embodiments of thepresent invention. In one embodiment of the present invention, themodules utilized by the control device 230 comprise software programcode and data that are executed or otherwise used by the processor 234,thereby causing the control device 230 to perform various actionsdictated by the software code of the various modules. The control devicecan also be in communication with a persistent data store that islocated remotely and is accessible over a computer network via a networkinterface 238, which implements communication frameworks and protocolsthat are well known to those of skill in the art.

In certain embodiments, the persistent memory device 236 containstranscranial magnetic stimulation application program code 242. Thecontrol device also includes a library of treatment protocol units 240for execution by the processor 234 in governing the operationalparameters of the magnetic assembly devices. The treatment protocolunits (TPUs) are, in one arrangement, data objects detailing specificoperational characteristics that are implementable by the magneticassembly devices. As is described in greater detail herein, one or moreTPUs may be sequentially combined to form a treatment protocol. TPUs canbe created locally or downloaded through the interface 238 from a remotesite.

The operational parameters of a given TPU comprise a series of key-valuepairs that users can define and which control operation of one or moremagnetic assembly devices. More generally, a treatment protocol unitdefines the manner in which one (and more typically at least two) ormore magnetic assembly devices are activated to create electric fieldsacross various areas of the brain of a subject over a window of time.Such information is used by the transcranial magnetic stimulationapplication program code to instruct the processor as to the manner inwhich to energize, via the controller, the set of magnetic assemblydevices to create such a field. The one or more TPUs includeinstructions to the controller for generating signals that causeindividual magnetic assembly devices to rotate. Receipt of such signalsfrom the controller by a given magnetic assembly device causes itsactuator to rotate its associated magnet at a particular frequency for aparticular duration. Such rotation of the magnet at a set frequencyresults in the generation of a desired electric field within the brain,which may be used as part of a therapy, diagnosis, mapping or othertreatment.

Advantageously, the transcranial magnetic stimulation applicationprogram code allows the user to select sets of treatment protocol units(TPUs) from library 240 to form one or more treatment protocols. TheTPUs can be considered as “units of stimulation” that can be combined toimplement specific treatments, referred to collectively as treatmentprotocols. A user interface can be provided by the transcranial magneticstimulation application program code, for example a graphical userinterface (GUI) or a text-based interface. Through the user interface,the user can define a set of TPUs that the processor applies to thesubject as a set treatment protocol or can select a preset protocolcomprising a set of TPUs defined locally or otherwise provided to thecontroller 232 from a remote site. As one example, in a neurologicalmedical facility, a doctor or other medical professional can treat apatient with Parkinson's disease by selecting a treatment protocol fromthe TPU library 240 tailored for this condition.

According to one embodiment, the transcranial magnetic stimulationapplication program code serially applies the TPUs comprising atreatment protocol (e.g, like a script). Alternatively, the transcranialmagnetic stimulation application program code may dynamically arrangeand apply the treatment protocol units comprising a given treatmentprotocol. Still further, the processor may execute and apply certaintreat protocol units in parallel, e.g., at the same time. The user mayalso share treatment protocols and TPUs with other users on othercontrol devices by way of a network that the control device accesses viaits network interface, which may further comprise receiving theindividual treatment protocol units comprising a received treatmentprotocol.

In one particular arrangement, the transcranial magnetic stimulationapplication program code instructs the processor 234 of the controldevice 230 to apply a treatment that utilizes one or more particularmagnetic assembly devices. The transcranial magnetic stimulationapplication program code can instruct the processor 234 to control theenergization of all, or a portion of the magnetic assembly devicespositioned on the transcranial system. An exemplary treatment protocolcan involve a specific pattern of TPUs, the application of which isdirected to the magnetic assembly device positioned in proximity to oneor more areas of the subject's brain, such as the Broca's Area. Theprocessor executing the transcranial magnetic stimulation applicationprogram code can generate a single control signal for distribution bythe controller that details the desired rotation frequencies, durations,quiescent periods or other conditions for each of the magneticassemblies. In other words, the user can select a treatment protocol andcause the system to implement a treatment or other procedure byimplementing the pattern of treatment protocol units, in parallel orserial, all based on the selection of a particular treatment protocol.

A TPU can be represented as a data object which serves to providestructure to a set of data regarding a treatment protocol, such as butnot limited to, rotation frequency, motor energization duration,quiescent period and specific energizing of a particular set of zero ormore magnetic assembly devices. The TPU is processed by the TMSapplication code 242 to establish the drive or quiescent settings foreach magnetic assembly device. TPUs can include a frequency valuerepresenting a rotational frequency for one or more magnetic assemblydevices, a rotational duration, a placement area for application of thetreatment protocol unit and a quiescent period, as example properties.TPUs can also implement a Theta Burst Stimulation (TBS) protocol. Here,the TBS protocol is defined as one or more active TPUs followed by asecond, quiescent TPU. In one particular example, the active TPU(s)defines a three (3) pulse pattern delivered at a frequency of 50 Hz,each pulse lasting 20 ms. A quiescent TPU lasting 160 ms defines aninter-burst interval from the last burst of the present pattern to thefirst burst of the next pattern. The active and quiescent TPSs combinefor a repeating treatment pattern of having a duration of 200milliseconds. While a single TPU can define a multiple burst pattern, itis also envisioned that the active TPUs defines a single burst. Thus, acollection of single burst TPUs (each without a period of quiescencefollowing the burst) followed by a single or collection of quiescentTPUs can also be used to define a TBS protocol.

In one or more implementations, execution of a particular TPU in atreatment protocol can cause issuance of a command to a single magneticassembly device for treating a localized area. Similarly, a giventreatment protocol unit may identify a set of one or more magneticassembly devices on the basis of the location(s) of such magnetic deviceassembly on the head mount which energize for rotation over a period oftime on the basis of the instructions in the given treatment protocolunit that the processor at the control device interprets. In anotherarrangement, magnetic assembly devices can be addressable on the basisof its connection point to the head mount, with the location of themagnetic device assembly being defined as a result of its connection tothe head mount by virtue of the attachment points. As a related matter,signal feedback concerning the operational capabilities/status of themagnetic assembly devices that are attached to the head mount and theirattachment points can coordinate with the system so as to permittreatment protocols to be selected, and to inform the clinician or othertreatment provider, patient or other user that additional or differentmagnetic assembly devices have to be attached, and where they have to beattached, before a particular treatment protocol is initiated.

As noted previously, a given TPU identifies one or more particularkey-value pairs that ultimately instruct the operational state of amagnetic assembly device at a given point in time. Accordingly, a givenTPU need not define each key-value pair contained within a giventreatment protocol unit, e.g., some keys can have a null or empty value.For example, a TPU can provide information about a quiescent period freeof any energization state information, e.g., frequency and durationvalues are set to null. In such a configuration, a quiescence-only TPUoperates as a break or spacer in the active sessions of a treatmentprotocol. In this way, quiescent periods can be introduced to accompanytreatment protocol units lacking a quiescent period. By way of example,treatment protocol units that only define a quiescent period can be usedto ensure that there is a set repetition frequency of between 0.1 to 2Hertz.

A treatment for a particular condition can be implemented as a group ofTPUs. According to one embodiment, the transcranial magnetic stimulationapplication program code instructs the processor to configure orassemble a set of TPUs according to an overall desired length oftreatment. For example, if the desired treatment is two minutes, thetranscranial magnetic stimulation application program code instructs theprocessor to assemble the TPUs into a treatment protocol is of thedesired length, such as by looping the TPUs that comprise the treatmentprotocol until the treatment duration has been achieved. Alternatively,longer duration TPUs can be used in a given treatment protocol toprovide a treatment program of a desired length. The resulting treatmentprotocol is a data object containing data used to instruct all or aportion of the magnetic assembly devices to generate a specific seriesof electric fields within the brain of the subject. Where differentmagnetic assembly devices mounted to the same cap 205 have differenttreatment protocol units applied, a treatment program dataset iscreated, which may be saved in a persistent data store as a library oftreatment protocols. Thus, a collection of treatment protocols can begenerated whereby different individual treatment protocols are used tocontrol one or more specific magnetic assembly devices at any giventime.

As described throughout, the processor at the control device executesthe transcranial magnetic stimulation program code to variably energizeone or more magnetic assembly devices spaced on the head mount 102 atlocations that span at least a portion of the cranium of a subject. Thecontrol device provides functionality for user selection of one or moretreatment protocols through interaction with the interface that theprocessor presents on a display device. The control device 230 mayprovide access to treatment protocols from local storage, as well astreatment protocols on remote data stores. According to one embodiment,the control device accesses a remote data store via a network throughuse of the network interface 238. Upon connection to the remote datastore, the control device copies the transaction protocol to localstorage for execution by the processor. Alternatively, the controldevice accesses the remote data store and reads transaction protocolinformation as needed, e.g., remote execution of the data.

The user can be presented with a listing of available treatmentprotocols, which may also comprise a listing of the individual treatmentprotocol units making up a given treatment protocol. Selection of agiven treatment protocol can be made on the basis of applying atreatment directed towards a particular ailment. For example, a dropdown menu can be provided in one embodiment by a graphical userinterface that can list i) a set of exemplary potential ailments thatrequire treatment, e.g.: depression, neurological and psychiatricdisorders, migraines, aphasia, anxiety, Parkinson's disease, tinnitus,autism, schizophrenia, Alzheimer's, ALS, stroke (e.g. ischemic),Myotonic Dystrophy type 1 (DM1), stuttering, epilepsy, Parkinson'sdisease, oncological diseases including but not limited to glioblastoma,pain and dystonia, cocaine, opioid and other addictive behaviors; ii)non-medical stimulation treatments such as for improved concentration,short and long-term memory, learning, foreign language training, etc. Auser can select a treatment protocol (comprising one or more treatmentprotocol units) that has been previously designed by another user, andpossibly already verified by peers, to ameliorate such conditions, orprovide such stimulus treatments. Alternatively, the user is free toselect one or more treatment protocol units depending on specificconditions or circumstances, for example, one or more collections oftreatment protocol units may be presented as having applicability to aparticular ailment, such as addiction or pain. The data store thatmaintains the treatment protocols and/or treatment protocol units can byassociated with metadata that functions as a suggestion as to theapplicability of a given treatment protocol unit or treatment protocol.

Optionally, information can be received from a database over the networkinterface which can define (e.g., constrain) the selection of treatmentprotocols to those that correspond to a prescription by a clinician orother treatment provider. Optionally, the set of treatment protocolsavailable for selection can be defined (e.g., constrained) as a functionof prior treatments. For instance, a treatment protocol can comprise aregimen of treatments in which the duration, energy, or other parametersare established for a patient or other user, yet which vary over thecourse of treatment. In this way, a predefined regimen of treatment canbe implemented (and repeated with the same or other subjects) withprecision by virtue of providing a series of treatment protocols througha predefined regimen.

During operation, the processor executes transcranial magneticstimulation program code 242 and retrieves TPUs from library 240 forexecution in series or in parallel. Upon execution of the TPUs, theprocessor issues instructions to the controller to activate (ordeactivate as the case may be) specific magnetic assembly devices whichcauses the motor or other actuator within a given magnetic assemblydevice to energize and induce the desired electrical fields within thebrain of the wearer or to de-energize, as the case may be.

Per the discussion of transcranial magnetic stimulation using treatmentprotocols above, it can be appreciated that the proper functioning ofeach of the actuated magnetic assembly devices is crucial in order todeliver treatments as intended. To ensure that the transcranial magneticstimulation apparatus performs properly on a regular basis, theproviders of the magnetic assembly devices can stipulate limitations onthe use of the devices by licensed use restrictions. For example, amagnetic assembly device can be licensed for a particular treatmentprotocol, for example, for treating Parkinson's disease, and the devicecan be licensed for a threshold number of uses under the license. Forexample, an assembly licensed for a Parkinson's treatment protocol canbe limited to 20 uses. While a centralized permission server can be usedto ensure that the magnetic assembly devices are used only under thelicensed restrictions, this solution requires connectivity with apermission server at every instance in which a magnetic assembly is usedduring a treatment. To avoid this dependence on connectivity with acentral authorizing entity, one embodiment of the invention uses ablockchain methodology to manage, monitor and control the usage of themagnetic assembly devices to ensure only licensed devices are used, andthat the licensed devices are used for only the permitted number oflicensed treatments.

Convergent Stimulation

Certain TPUs intended to treat particular conditions can targetsubcortical brain locations. As it is known that magnetic flux andinduced voltage magnitude drop quickly with depth (proportional to 1/r³)special care is taken to ensure that the induced voltage generated atthe location is sufficient to provide neurostimulation. The strength ofthe magnetic flux provided by an individual magnetic assembly isdetermined by the size of the magnet, the strength of the magneticmaterial and the rotational speed at which the magnet is rotated. Forneurostimulation, additional factors including the neuronal environmentand physiology also come into play. The equation for determining fluxdensity B(t) at the targeted simulation site is modeled as asuperposition of magnetic dipole fields as follows:

$\begin{matrix}{{B(t)} = {\frac{\mu_{0}}{4\;\pi}{\sum( {\frac{3{r_{i}( {{m_{i}(t)} \cdot r_{i}} }}{r_{i}^{5}} - \frac{m_{i}(t)}{r_{i}^{3}}} )}}} & (1)\end{matrix}$

in which m_(i)(t) is the magnetic moment of magnet (i) and r_(i) is thedistance between the center of the magnet and the targeted stimulationsite. FIG. 4 is a schematic illustration showing magnetic fieldsproduced by three magnets and the penetration of the fields in the brainof the patient. The distance between a first magnet and the stimulationsite is r₁, the distance between a second magnet and the stimulationsite is r₂, and the distance between a third magnet and the stimulationsite is r₃. The resultant magnetic flux B(t) at the stimulation site isthe sum of the magnetic field produced by each of the three magnetsaccording to equation (1) above. If the magnets themselves areidentical, the distances r₁, r₂, r₃ determine the magnitude of themagnetic flux at the stimulation site.

However, it is not the magnetic flux B(t) that is the determining factorfor neuronal stimulation but rather it is the induced electric field atthe stimulation site U(t). The induced voltage in a surrounding area Ais calculated as follows:

$\begin{matrix}{{U(t)} = {- {\int{\frac{d\;{B(t)}}{dt} \cdot {dA}}}}} & (2)\end{matrix}$

From the dB(t)/dt term, the induced voltage is proportional to rate ofchange of the magnetic flux, which is in turn proportional to therotational speed (frequencies) of the permanent magnets. Therefore,increasing the rotation rate of the magnets is one way to provide higherinduced voltage using the same magnet size and type. FIG. 5 is a graphshowing an example of voltages induced by TRPMS magnets at a stimulationsite. The TRPMS stimulation is an oscillation that rises and falls inamplitude and frequency, and plateaus at a peak amplitude and frequencyin between. The amplitude varies with magnet-to-simulation sitedistance, but the duration of the responses and frequency of the inducedvoltage oscillations do not change with distance. The amplitude of theinducted voltage signal reaches a stable peak in 75-150 ms.

One of the advantages of TRPMS in comparison with TMS (which useselectromagnetic coils) is that the spatial spread of the voltageinducted by a plurality of TRPMS magnets is narrow in the X-Y plane(perpendicular to the depth(z) direction). The narrow spatial spread ofthe induced voltage enables focused stimulation of localized brainregions. This is shown in FIGS. 6A and 6B which are graphs showinginduced voltages at different depths along the left-right (X) direction(FIG. 6A) and backward-forward (Y) direction, respectively. As thegraphs indicate, the voltages induced by TRPMS fall to negligible levels2 centimeters away from the central focus of stimulation.

While TRPMS typically does not provide as much amplitude at depth asTMS, high induced voltages at depth can be obtained by a) focusing themagnetic flux generated by plurality of magnetic fields on the samelocation to combine the effects of multiple magnets and/or b) scaling upthe power of each magnet, by increasing the size and/or strength of themagnets. FIG. 7 is a graph indicating how high induced voltages can beachieved at depth through the latter method of scaling up the power ofthe magnets. In the data shown in FIG. 7, the upper curve 400 representsdata from larger rotating permanent magnets that would be lessconvenient to mount but nevertheless show that an 8-fold increase ininduced voltage at depths of as high as 4-5 cm can be achieved usingpermanent magnets. Mountable versions of the magnetic assemblies can beimplemented by using extra high-strength magnets to avoid undulyincreasing the size of the magnets and to retain the utility of havingthese mounted on a cap that rests on the person's head or on a devicethat is otherwise positioned to be in contact with the person using it.

More generally, the strategy of combining the effects of multipleco-focused permanent magnets acting in concert on a localized brainregion enables the use of regular (smaller) sized magnetic assembliesthat can be conveniently coupled to a head mount. In certainimplementations in which brain regions at high depths (>6 cm) aretargeted for treatment, a combined strategy can be used. That is,small-sized magnets used in the magnetic assemblies on a head mount canbe constructed with extra high strength materials, or regular-strengthsmall-sized magnets can be combined with one or more larger sizedmagnets that can be coupled to the head mount according to specificrequirements of the treatment.

In accordance with a salient aspect of this disclosure, the inducedvoltages used for a number of the treatments discussed above can bemaintained below the level required to stimulate skeletal muscularmovement, referred to as motor-evoked potentials (MEPs). Rather, it isfound that induced electric fields in the ˜12-30 V/m change, which areconsiderably below the MEP level, are sufficient to induce a significantincrease in the frequency of spontaneously occurring fasciculationpotentials or sMUPs. Such neurological activity has also been shown tobe associated with therapeutic and other benefits across a range ofconditions. FIGS. 8A and 8B provide a schematic illustration of thecapability of magnetic assemblies of the present disclosure acting inconcert to produce a convergent field. In FIG. 8A, magnetic assemblieswith rotating permanent magnets 502, 504, 506 are positioned on theskull 510 of patient and each generate a magnetic field sufficient toinduce voltages in the brain of a patient. The magnetic field generatedby magnetic assembly 502 induces an envelope of electric field in alocalized region of the patient's brain labeled 512. Similarly, themagnetic field generated by magnetic assembly 504 induces an envelope ofelectric field in area 514, and magnetic assembly 506 induces andenvelope of electric field above the threshold in brain area 516. Asshown, the envelopes 512, 514, 516 taper with depth in the brain,indicating that the induced electric field at depth decreases. Inaddition, the envelopes 512, 514 and 516 are distinct and do notoverlap.

At a certain depth, the magnitude of the induced field generated by anysingle magnet might not be sufficient to generate SMUPs or otherneuronal activity sufficient (e.g., each might be <12 V/m) to achieve adesired response at a targeted depth. This is the case in theillustration of FIG. 8A in which the envelopes of induced electric field512, 514 do not overlap and do not combine at a deep location in thebrain of the patient. By contrast, in FIG. 8B, magnetic assemblies 522,524, 526 are selectively positioned so that the respective envelopes ofinduced electric fields 532, 534, 536 that they generate in thepatient's brain converge at a subcortical brain region 550 (shown by thedashed ellipse). As the induced electric fields are additive, the totalelectric field induced in region 550 can be greater than the thresholdrequired to achieve stimulation of SMUPs, or other effectiveneuromodulation, and the total electric field can remain at a levelwhich is insufficient to stimulate skeletal muscular movement (below theMEP potential).

The combined electric fields are set at a strength necessary to achievean effect on brain structures in the overlapping region 550. It is alsoimportant, however, to set the field strengths so that the effect of theelectric field in non-overlapping portions of envelopes 532, 534, 536 isinsufficient to produce undesired effects in the respectivenon-overlapping regions. In other words, the electric field strength isset so that it is smaller, particularly at shallow regions along thepathways of the electric field within each envelope 532, 534, 536 towardthe overlapping region 550, than the field strength in the overlappingregion where the electric field of the envelopes converge and combine.Setting the electric field strength with this in mind avoids unintendedstimulation of brain structures in brain regions outside of theoverlapping region 550.

By positioning the magnetic assemblies in locations in which theirrespective magnetic fields can act in concert at a targeted cortical orsubcortical brain location, effective neuromodulation useful fortreating, improving or otherwise effecting a variety of neurobiologicalconditions is possible. The positions at which the magnetic assembliesare set will depend on the brain region targeted, the amount of inducedvoltage required, and the characteristics of the magnetic assemblies(e.g., orientation, size, magnetic material, spin rate), among otherfactors. In some implementations, the convergent magnetic fields can bedelivered simultaneously. In other implementations, the magnetic fieldscan be delivered sequentially and still achieve a similar additiveeffect.

Localized stimulation or modulation can be increased, in some instances,by controlling the rotating magnetic assemblies to rotate at differentrates. The superposition of electromagnetic signals of differentfrequency produces a difference signal with a lower frequency which can,in certain circumstances and in certain brain regions, have a moredramatic effect than higher frequency signals alone. The rotation rateof each of the magnetic assemblies can be controlled individually toproduce such effects.

Recent research has shown that the induction of electric fields in thebrain using TRPMS can have additional effects beyond neurostimulation.For example, cortical or sub-cortical induced electric fields can causedepolarization of mitochondrial membrane potentials (MMP) and altermitochondrial oxidation in brain tissue. This alteration in oxidationappears to lead to disruption of mitochondrial networks and canultimately cause apoptosis in tumor cells. Therefore, selectivetargeting of tumor cells using convergent magnetic fields from aplurality of rotating magnets shows promise as a useful non-invasiveoncological treatment through this mitochondrial disruption pathway.Furthermore, as mitochondrial activity is crucial to almost allbiological functioning, modulation of such function using convergentTRPMS has wide application and can affect a multitude of normal orpathological conditions.

More generally, the convergent induced electric fields in brain regionscan be used to affect the behavior of polar molecules. As discussed, forexample in “Magnetic Field Application and its Potential in Water andWastewater Treatment Systems” by N. Saidi et al. (Separation andPurification Reviews (2014)), polar molecules are affected strongly bystatic magnetic fields and dynamic magnetic fields (through theinfluence of the induced electric field). Many vital cellular processesrely specifically on the polarity of functional molecules. As animportant example, cell division is mediated by tubulin and septinproteins which are both polar molecules. In order for cell division tooccur these proteins must be positioned and aligned in a specific way.The induction of electric fields by TPRMS in specific brain regions canbe used to disrupt or interfere with the timing of such positioning andalignment of tubulin and septin proteins, and can thereby affect therate and timing of cell division in targeted brain regions.

Since TRPMS can deliver highly focal stimuli that can be scaled and itprovides a way of delivering imperceptible multifocal stimulisimultaneously, sequentially and in defined spatiotemporal patterns, themagnetic assemblies can be used in concert to provide convergentstimulation and can also be scaled up. The controller enables thestimulus parameters and sites of stimulation to be varied dynamicallyusing real time feedback. In addition, the stimulation can effectivelyinfluence a variety of neuronal patterns and geometries because themagnetic field direction can sweep over a continuum of angles, dependingon the configuration of the magnets.

While this specification contains many specific embodiment details,these should not be construed as limitations on the scope of anyembodiment or of what can be claimed, but rather as descriptions offeatures that can be specific to particular embodiments of particularembodiments. Certain features that are described in this specificationin the context of separate embodiments can also be implemented incombination in a single embodiment. Conversely, various features thatare described in the context of a single embodiment can also beimplemented in multiple embodiments separately or in any suitablesub-combination. Moreover, although features can be described above asacting in certain combinations and even initially claimed as such, oneor more features from a claimed combination can in some cases be excisedfrom the combination, and the claimed combination can be directed to asub-combination or variation of a sub-combination.

Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. In certain circumstances, multitasking and parallel processingcan be advantageous. Moreover, the separation of various systemcomponents in the embodiments described above should not be understoodas requiring such separation in all embodiments, and it should beunderstood that the described program components and systems cangenerally be integrated together in a single software product orpackaged into multiple software products.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising”, when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof.

It should be noted that use of ordinal terms such as “first,” “second,”“third,” etc., in the claims to modify a claim element does not byitself connote any priority, precedence, or order of one claim elementover another or the temporal order in which acts of a method areperformed, but are used merely as labels to distinguish one claimelement having a certain name from another element having a same name(but for use of the ordinal term) to distinguish the claim elements.Also, the phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having,” “containing,” “involving,” andvariations thereof herein, is meant to encompass the items listedthereafter and equivalents thereof as well as additional items.

Particular embodiments of the subject matter described in thisspecification have been described. Other embodiments are within thescope of the following claims. For example, the actions recited in theclaims can be performed in a different order and still achieve desirableresults. As one example, the processes depicted in the accompanyingfigures do not necessarily require the particular order shown, orsequential order, to achieve desirable results. In certain embodiments,multitasking and parallel processing can be advantageous.

Publications and references to known registered marks representingvarious systems are cited throughout this application, the disclosuresof which are incorporated herein by reference. Citation of any abovepublications or documents is not intended as an admission that any ofthe foregoing is pertinent prior art, nor does it constitute anyadmission as to the contents or date of these publications or documents.All references cited herein are incorporated by reference to the sameextent as if each individual publication and references werespecifically and individually indicated to be incorporated by reference.

While the invention has been particularly shown and described withreference to a preferred embodiment thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention. As such, the invention is not defined by the discussion thatappears above, but rather is defined by the claims that follow, therespective features recited in those points, and by equivalents of suchfeatures.

1-21. (canceled)
 22. A method of stimulating or modifying a biological,cellular or biochemical function or structure in a targeted subcorticallocation in a brain of a patient using a TRPMS (Transcranial RotatingPermanent Magnetic System) apparatus provided on a head mount, theapparatus having a plurality of releasable magnetic assemblies withrotating permanent magnets operable to rotate for controlled durationsand spin rates, the method comprising: positioning two or more of theplurality of magnetic assemblies at locations of the head mount selectedto stimulate the targeted subcortical location in the brain of thepatient; and activating the plurality of magnetic assemblies to generatemagnetic fluxes of a selected strength, frequency and duration to bedirected into the brain of the patient and which are operative togenerate an induced electric field in regions of the brain; wherein theregions of induced electric fields generated by each of the plurality ofmagnetic assemblies converge and overlap in the targeted subcorticallocation and combine to a magnitude sufficient to stimulate or modifythe biological, cellular or biochemical function or structure in thetargeted subcortical location.
 23. The method of claim 22, wherein theinduced electric field in regions of the brain from each of theplurality of magnetic assemblies has a pathway toward the targetedsubcortical location, and wherein activation of each of the plurality ofmagnetic assemblies is at the electric field strength which avoidsstimulation of brain structures in brain regions along a respectivepathway while outside of the targeted subcortical location.
 24. Themethod of claim 22, wherein the targeted subcortical location is atleast 2 centimeters deep as measured from an external surface of thebrain.
 25. The method of claim 22, wherein the regions of inducedelectric fields generated by each of the plurality of magneticassemblies combine to a magnitude sufficient to modulate mitochondrialactivity in the targeted subcortical location.
 26. The method of claim25, wherein modulation of the mitochondrial activity in the targetedsubcortical location causes apoptosis of oncological tumor cells in thetargeted location.
 27. The method of claim 22, wherein the regions ofinduced electric fields generated by each of the plurality of magneticassemblies combine to a magnitude sufficient to modify a position ororientation of polar molecules involved in a cellular process in thetargeted subcortical location.
 28. The method of claim 27, wherein theregions of induced electric fields generated by each of the plurality ofmagnetic assemblies combine to a magnitude sufficient to modify aposition or orientation of at least one of septin and tubulin toregulate cell division in the targeted subcortical location.
 29. Themethod of claim 22, wherein the combined electric fields at the targetedsubcortical location has a magnitude at or above 12 V/m.
 30. The methodof claim 29, wherein the combined electric fields at the targetedsubcortical location has a magnitude in a range of about 12 V/m to about30 V/m.
 31. The method of claim 22, wherein the regions of inducedelectric fields generated by each of the plurality of magnetic combineto a magnitude sufficient to increase a frequency of spontaneouslyoccurring fasciculation potentials (sMUPs) of neurons in the targetedsubcortical location.